A Phase 1b, Dose Escalation/Dose Expansion, Multicenter, Open-Label Study to Assess the Safety and Tolerability of OPN-6602 Monotherapy and in Combination with Dexamethasone in Subjects with Relapsed and/or Refractory Multiple Myeloma

Background and Significance:

OPN-6602 is a potent, selective, and orally active small molecule dual cyclic-AMP response element-binding protein (CBP) and E1A binding protein (EP300) bromodomain (BRD) inhibitor. It has low nanomolar potency against EP300 and CBP, with greater than 100-fold less activity against BRD3, which was the most potent among all the other BRDs evaluated. OPN-6602 suppresses known oncogenes interferon regulatory factor 4 (IRF4) with downstream suppression of MYC resulting in antitumor activity through EP300/CBP inhibition. It is a potent inhibitor of multiple myeloma (MM) cell growth in the MM cell lines, OPM-2 and MM.1S, and a potent inhibitor of histone acetylation via BRD intramolecular modulation of histone acetyltransferase (HAT) activity. EP300 and CBP are transcription coactivators that contain both epigenetic writer HAT and reader BRDs that regulate transcription of genes via chromatin remodeling. EP300 and CBP are highly conserved and ubiquitously expressed enzymes that belong to the KAT3 family of acetyltransferases. EP300 and CBP interact with numerous other proteins to function as global transcriptional coactivators through the modification of lysines on both histone and non-histone nuclear proteins, affecting proteins such as IRF4 and MYC. IRF4/MYC act as lineage-specific transcription factors controlling the survival and growth of MM. EP300/CBP inhibition causes cell cycle arrest and apoptosis in MM through suppression of IRF4 and MYC, rendering EP300/CBP as a novel target for MM (Conery 2016). Recently, unbiased analysis of vulnerability genes identified EP300 as a specific and highly relevant target for MM (de Matos Simoes 2023).

OPN-6602 pharmacokinetic (PK) studies in mice, rats, and dogs consistently showed moderate clearance and short terminal half-life. In definitive 28-day GLP toxicology studies, OPN-6602 showed near dose-proportional increases in exposure over the dose range evaluated. These PK properties were specifically engineered to enable daily ‘pulsatile’ dosing. The potent selective inhibition of EP300 and CBP can be exploited to address several unmet medical needs through different mechanisms. In particular, a selective inhibitor of EP300 and CBP such as OPN-6602 has the potential to be a promising treatment for MM.

Study Design and Methods:

Study OPN6602-C01 is a Phase 1b, open-label study evaluating the safety, tolerability, PK, preliminary antitumor activity, and pharmacodynamics of OPN-6602 monotherapy and in combination with dexamethasone in subjects with relapsed and/or refractory MM. OPN-6602 as monotherapy or in combination with dexamethasone will be administered orally once daily in 21-day cycles. This study consists of 3 parts: Part 1a OPN-6602 monotherapy dose escalation (Part 1a), Part 1b OPN-6602 combination with dexamethasone dose escalation (Part 1b), and Part 2 dose expansion of the preferred regimen (Part 2) to select and optimize the dose with 1:1 randomization of at least 2 potential dose levels of 20 subjects at each dose level (ie, the provisional recommended Phase 2 dose [RP2D] identified in Part 1a or Part 1b and 1 additional dose level). Either OPN-6602 monotherapy or OPN-6602 in combination with dexamethasone will be selected for Part 2. Up to 130 total evaluable subjects will be enrolled across dose escalation and dose expansion.

The primary objective and endpoint for Part 1a and Part 1b is to characterize the tolerability of OPN-6602 (with and without dexamethasone). Dose limiting toxicities, treatment-emergent adverse events and changes in safety and lab parameters will be characterized in order to identify the RP2D. The primary objective and endpoint for dose expansion of OPN-6602 monotherapy or in combination with dexamethasone is to evaluate the preliminary antitumor activity using overall response rate based on the 2011 International Myeloma Working Group (IMWG) response criteria.

Eligibility criteria include a confirmed diagnosis of MM per IMWG criteria, disease that is relapsed or refractory to 3 or more different prior lines of therapy that include immunomodulatory agents, proteasome inhibitors and an anti-CD38 antibody, measurable disease and adequate hematologic, renal and liver function.

This multi-center study (NCT06433947) is currently open in the United States with additional sites planned to open in Switzerland, United Kingdom and the European Union.

Walling:Opna Bio: Consultancy, Current Employment. Matusow:Opna Bio LLC: Current Employment, Current holder of stock options in a privately-held company. Nichols:Opna Bio: Current Employment, Current holder of stock options in a privately-held company. Singh:Opna Bio: Current Employment, Current holder of stock options in a privately-held company. Inokuchi:Opna Bio: Current Employment, Current holder of stock options in a privately-held company. Bollag:Opna Bio: Current Employment, Current holder of stock options in a privately-held company.